CN114621163A - Refining method of sofosbuvir intermediate - Google Patents
Refining method of sofosbuvir intermediate Download PDFInfo
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- CN114621163A CN114621163A CN202011443557.4A CN202011443557A CN114621163A CN 114621163 A CN114621163 A CN 114621163A CN 202011443557 A CN202011443557 A CN 202011443557A CN 114621163 A CN114621163 A CN 114621163A
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- Prior art keywords
- benzoyloxy
- methyl
- fluoro
- butyrolactone
- refining method
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- 238000007670 refining Methods 0.000 title claims abstract description 16
- 238000000034 method Methods 0.000 title claims abstract description 14
- TTZHDVOVKQGIBA-IQWMDFIBSA-N sofosbuvir Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@]2(F)C)O)CO[P@@](=O)(N[C@@H](C)C(=O)OC(C)C)OC=2C=CC=CC=2)C=CC(=O)NC1=O TTZHDVOVKQGIBA-IQWMDFIBSA-N 0.000 title claims abstract description 12
- 229960002063 sofosbuvir Drugs 0.000 title claims abstract description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 20
- FOMXZKGSBUZQHO-HSALFYBXSA-N C[C@@]([C@H](OC(C1=CC=CC=C1)=O)OC1=O)([C@@]1(C)F)OC(C1=CC=CC=C1)=O Chemical compound C[C@@]([C@H](OC(C1=CC=CC=C1)=O)OC1=O)([C@@]1(C)F)OC(C1=CC=CC=C1)=O FOMXZKGSBUZQHO-HSALFYBXSA-N 0.000 claims abstract description 15
- 239000012043 crude product Substances 0.000 claims abstract description 12
- 239000012065 filter cake Substances 0.000 claims abstract description 12
- 238000001914 filtration Methods 0.000 claims abstract description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000003756 stirring Methods 0.000 claims abstract description 8
- 238000001035 drying Methods 0.000 claims abstract description 6
- 238000010438 heat treatment Methods 0.000 claims abstract description 6
- 238000004537 pulping Methods 0.000 claims abstract description 6
- 238000010992 reflux Methods 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 3
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- 238000001704 evaporation Methods 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims 3
- 230000003247 decreasing effect Effects 0.000 claims 1
- 238000001816 cooling Methods 0.000 abstract description 5
- 230000003321 amplification Effects 0.000 abstract description 2
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 2
- 239000003814 drug Substances 0.000 description 7
- 208000005176 Hepatitis C Diseases 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 229960000329 ribavirin Drugs 0.000 description 3
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 208000006154 Chronic hepatitis C Diseases 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 208000022120 Jeavons syndrome Diseases 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 208000010710 hepatitis C virus infection Diseases 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229940076563 sovaldi Drugs 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The application discloses a refining method of a sofosbuvir intermediate, which comprises the following steps: 1) dissolving the crude product (2R,3R,4R) -2-fluoro-2-methyl-3-benzoyloxy-4- (benzoyloxy) methyl-4-butyrolactone in isopropanol, and heating and refluxing to dissolve the crude product; 2) distilling under normal pressure, and keeping constant speed and cooling to 10-20 ℃ after 1/3 solvent is evaporated; 3) stirring and crystallizing at 10-20 ℃, filtering, adding n-hexane into a filter cake, pulping, filtering, and drying the filter cake to obtain the refined (2R,3R,4R) -2-fluoro-2-methyl-3-benzoyloxy-4- (benzoyloxy) methyl-4-butyrolactone. The invention provides an effective refining method, which is characterized in that a (2R,3R,4R) -2-fluoro-2-methyl-3-benzoyloxy-4- (benzoyloxy) methyl-4-butyrolactone crude product obtained after reaction post-treatment is refined to more than 98.5 percent through one-time refining. The refining method of the invention has no special equipment requirement, is simple to operate and is suitable for industrial amplification.
Description
Technical Field
The invention belongs to the field of biological medicines, and particularly relates to a refining method of a sofosbuvir intermediate.
Background
Sofosbuvir (also known as Sofosbuvir, the english name Sofosbuvir, trade name Sovaldi) is a new drug developed by gilide corporation for the treatment of chronic hepatitis c and is approved by the U.S. Food and Drug Administration (FDA) to be marketed in the united states at 12/6 d in 2013 and by the european drug administration (EMEA) at 16 d 1/2014. The medicine is the first medicine which can safely and effectively treat certain types of hepatitis C without combining interferon. Clinical trials demonstrated that the overall sustained virological response rate (SVR) of this drug in combination with peginterferon and ribavirin was as high as 90% for type 1 and 4 hepatitis c; aiming at type 2 hepatitis C, the SVR of the medicine and ribavirin is 89-95 percent; for type 3 hepatitis C, the SVR of the drug in combination with ribavirin is 61% -63%. The compound 1 shown as the following formula, (2R,3R,4R) -2-fluoro-2-methyl-3-benzoyloxy-4- (benzoyloxy) methyl-4-butyrolactone is a key intermediate of sofosbuvir, and in the introduction process of fluorine atoms, impurities with alpha and beta positions substituted by Cl or OH can be formed due to the existence of trace amounts of Cl, OH and the like in a system, and a small amount of beta substituted F isomer also exists, so that certain difficulty is caused in refining the intermediate.
Disclosure of Invention
The main purpose of the application is to provide a refining method of a sofosbuvir intermediate.
The technical scheme is as follows:
a refining method of a sofosbuvir intermediate comprises the following steps:
1) dissolving the crude product (2R,3R,4R) -2-fluoro-2-methyl-3-benzoyloxy-4- (benzoyloxy) methyl-4-butyrolactone in isopropanol, and heating and refluxing to dissolve the crude product;
2) distilling at normal pressure, evaporating 1/3 solvent, and keeping constant speed to cool to 10-20 ℃;
3) stirring and crystallizing at 10-20 ℃, filtering, adding n-hexane into a filter cake, pulping, filtering, and drying the filter cake to obtain the refined (2R,3R,4R) -2-fluoro-2-methyl-3-benzoyloxy-4- (benzoyloxy) methyl-4-butyrolactone.
Further, the weight percentage of the crude product (2R,3R,4R) -2-fluoro-2-methyl-3-benzoyloxy-4- (benzoyloxy) methyl-4-butyrolactone and isopropanol in step 1) is 1 w: 5-15 v; preferably 1 w: 10 v.
Further, the temperature rise temperature in the step 1) is 70-90 ℃.
Further, the uniform cooling rate in the step 2) is 15 ℃ per hour.
Further, the stirring crystallization time in the step 3) was 2 hours.
The invention provides an effective refining method, which is characterized in that a (2R,3R,4R) -2-fluoro-2-methyl-3-benzoyloxy-4- (benzoyloxy) methyl-4-butyrolactone crude product obtained after reaction post-treatment is refined to more than 98.5 percent through one-time refining. The refining method of the invention has no special equipment requirement, is simple to operate and is suitable for industrial amplification.
Detailed Description
In order to make those skilled in the art better understand the technical solutions in the present application, the technical solutions in the embodiments of the present application will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present application, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present application.
Example 1
Adding 50g of the crude product of the compound 1 into a reaction bottle, adding 500ml of isopropanol, heating to about 80 ℃, refluxing to clear solution, switching to normal pressure distillation after confirming the clear solution, concentrating to obtain about 150ml of isopropanol until the system is slightly turbid, maintaining the temperature at 15 ℃ per hour, cooling to 10-20 ℃, stirring at 10-20 ℃ for crystallization for 2 hours, filtering, transferring a filter cake to the reaction bottle, adding 100ml of n-hexane for pulping for 2 hours, filtering, and drying the filter cake to obtain 43.2g of (2R,3R,4R) -2-fluoro-2-methyl-3-benzoyloxy-4- (benzoyloxy) methyl-4-butyrolactone, wherein the yield is 86.4 percent, and the purity is 98.8 percent.
Example 2
Adding 45g of the crude product of the compound 1 into a reaction bottle, adding 400ml of ethanol, heating to about 80 ℃, refluxing to clear solution, switching to normal pressure distillation after confirming the clear solution, concentrating to obtain about 100ml of isopropanol until the system is slightly turbid, maintaining the temperature at 15 ℃ per hour, cooling to 10-20 ℃, stirring at 10-20 ℃ for crystallization for 2 hours, filtering, transferring a filter cake to the reaction bottle, adding 90ml of n-hexane for pulping for 2 hours, filtering, and drying the filter cake to obtain 37.4g of (2R,3R,4R) -2-fluoro-2-methyl-3-benzoyloxy-4- (benzoyloxy) methyl-4-butyrolactone, wherein the yield is 83.11%, and the purity is 98.6%.
Example 3
Adding 50g of the crude product of the compound 1 into a reaction bottle, adding 600ml of n-propanol, heating to about 80 ℃, refluxing to clear solution, switching to normal pressure distillation after confirming the clear solution, concentrating to obtain about 200ml of isopropanol until the system is slightly turbid, maintaining the temperature at 15 ℃ per hour, cooling to 10-20 ℃, stirring at 10-20 ℃ for crystallization for 2 hours, filtering, transferring a filter cake to the reaction bottle, adding 100ml of n-hexane for pulping for 2 hours, filtering, and drying the filter cake to obtain 39.6g of (2R,3R,4R) -2-fluoro-2-methyl-3-benzoyloxy-4- (benzoyloxy) methyl-4-butyrolactone, wherein the yield is 79.2 percent, and the purity is 98.9 percent.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (6)
1. A refining method of a sofosbuvir intermediate is characterized by comprising the following steps:
1) dissolving the crude product (2R,3R,4R) -2-fluoro-2-methyl-3-benzoyloxy-4- (benzoyloxy) methyl-4-butyrolactone in isopropanol, and heating and refluxing to dissolve the crude product;
2) distilling at normal pressure, evaporating 1/3 solvent, and keeping constant speed to cool to 10-20 ℃;
3) stirring and crystallizing at 10-20 ℃, filtering, adding n-hexane into a filter cake, pulping, filtering, and drying the filter cake to obtain the refined (2R,3R,4R) -2-fluoro-2-methyl-3-benzoyloxy-4- (benzoyloxy) methyl-4-butyrolactone.
2. The purification process according to claim 1, wherein the weight percentage of the crude (2R,3R,4R) -2-fluoro-2-methyl-3-benzoyloxy-4- (benzoyloxy) methyl-4-butyrolactone in step 1) to isopropanol is 1 w: 5-15 v.
3. The purification process according to claim 1, wherein the weight percentage of the crude (2R,3R,4R) -2-fluoro-2-methyl-3-benzoyloxy-4- (benzoyloxy) methyl-4-butyrolactone in step 1) to isopropanol is 1 w: 10 v.
4. The refining method according to claim 1, wherein the temperature in the step 1) is raised to 70 to 90 ℃.
5. The refining process of claim 1, wherein the step 2) of uniformly decreasing the temperature is at a rate of 15 ℃ per hour.
6. The purification process according to claim 1, wherein the crystallization time with stirring in the step 3) is 2 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011443557.4A CN114621163A (en) | 2020-12-11 | 2020-12-11 | Refining method of sofosbuvir intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011443557.4A CN114621163A (en) | 2020-12-11 | 2020-12-11 | Refining method of sofosbuvir intermediate |
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| Publication Number | Publication Date |
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| CN114621163A true CN114621163A (en) | 2022-06-14 |
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| CN202011443557.4A Pending CN114621163A (en) | 2020-12-11 | 2020-12-11 | Refining method of sofosbuvir intermediate |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105085445A (en) * | 2015-08-11 | 2015-11-25 | 海门慧聚药业有限公司 | Preparation method of Sofosbuvir intermediate |
| CN105503787A (en) * | 2015-12-31 | 2016-04-20 | 阜阳欣奕华材料科技有限公司 | Sofosbuvir intermediate purification method |
| WO2016098123A2 (en) * | 2014-12-16 | 2016-06-23 | Laurus Labs Private Ltd | A recycling process for preparing (s)-2-[(substituted-phenoxy)-phenoxy- phosphorylamino] propionic acid isopropyl ester diastereomers |
| CN106146433A (en) * | 2015-03-26 | 2016-11-23 | 常州制药厂有限公司 | A kind of preparation method of the intermediate of Suo Feibuwei |
| CN107245064A (en) * | 2017-05-19 | 2017-10-13 | 福安药业集团宁波天衡制药有限公司 | The preparation of Suo Feibuwei intermediates and by-product recovery method |
| CN109422710A (en) * | 2017-08-28 | 2019-03-05 | 常州制药厂有限公司 | A kind of preparation method of Suo Feibuwei fluorine lactone intermediate |
-
2020
- 2020-12-11 CN CN202011443557.4A patent/CN114621163A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016098123A2 (en) * | 2014-12-16 | 2016-06-23 | Laurus Labs Private Ltd | A recycling process for preparing (s)-2-[(substituted-phenoxy)-phenoxy- phosphorylamino] propionic acid isopropyl ester diastereomers |
| CN106146433A (en) * | 2015-03-26 | 2016-11-23 | 常州制药厂有限公司 | A kind of preparation method of the intermediate of Suo Feibuwei |
| CN105085445A (en) * | 2015-08-11 | 2015-11-25 | 海门慧聚药业有限公司 | Preparation method of Sofosbuvir intermediate |
| CN105503787A (en) * | 2015-12-31 | 2016-04-20 | 阜阳欣奕华材料科技有限公司 | Sofosbuvir intermediate purification method |
| CN107245064A (en) * | 2017-05-19 | 2017-10-13 | 福安药业集团宁波天衡制药有限公司 | The preparation of Suo Feibuwei intermediates and by-product recovery method |
| CN109422710A (en) * | 2017-08-28 | 2019-03-05 | 常州制药厂有限公司 | A kind of preparation method of Suo Feibuwei fluorine lactone intermediate |
Non-Patent Citations (1)
| Title |
|---|
| 朱明军、梁世中: "化学制药工艺学", 中国医药科技出版社, pages: 335 - 352 * |
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